This invention relates to a process for the manufacture of the antibiotic 7-(D-.alpha.-amino-.alpha.-phenyl acetamido)-3-methyl-3-cephem-4-carboxylic acid (cephalexin) of the formula 1: ##STR1## and pharmaceutically acceptable salts thereof.
The antibiotic of the formula 1 is well known as perorally active antibacterial having broad spectrum activity. Several processes for the manufacture of the compound of the formula 1 are reported.
U.S. Pat. Nos. 3,507,861, 3,671,449, 3,634,416 and 3,676,437 relate to the manufacture of compound of the formula 1 by esterification of 7-amino Desacetoxy Cephalosporanic Acid (7-ADCA) of the formula 2: ##STR2## with reagents containing ester groups such as 2,2,2-trichloromethyl, p-nitrobenzyl or trlmethyl silyl to obtain ester protected 7-ADCA derivative ot the formula 3: ##STR3## wherein Z.sub.1 is ester group such as 2,2,2-trichloromethyl, p-nitrobenzyl or trimethysilyl followed by condeneation with a mixed anhydride of the formula 4: ##STR4## wherein R.sub.1 is methyl or ethyl and R2 is ethyl or tertiary butyl obtained by reacting D-(-)-.alpha. phenyl glycine derivative (Dane salt) of the formula 5: ##STR5## wherein R.sub.1 is as defined above with an acid chloride of the formula R.sub.2 --COCl, wherein R.sub.2 is as defined above. The resulting compound of the formula 6a: ##STR6## wherein R.sub.1 and Z.sub.1 are as defined above is hydrolysed with an aqueous mineral acid to cleave the ester group and obtain the compound of the formula 1. The procedures for isolation and purification of the compound of the formula 1 from the reaction mixture are complicated and difficult due to the ester functionality. Therefore, these processes are difficult and inconvenient to carry out. Besides these processes give the compound of the formula 1 in low yield (50%) and low purity and are not economical and commercially viable.
U.S. Pat. No. 3,518,260 relates to the manufacture of compound of the formula 1 by dissolving 7-ADCA of the formula 2 in water and subsequently condensing with mixed anhydride of the formula 4 obtained by reacting Dane salt of the formula 5 with an acid chloride of the formula R.sub.2 --COCl in acetone. The resulting compound of the formula 6b: ##STR7## wherein R.sub.1 is as defined above and Z.sub.2 is an alkyl amine such as triethyl amine is hydrolyzed with an aqueous mineral acid to cleave the enamine protected group and give the compound of the formula 1. This process suffers from dismal yields as low as 25 to 40% of the compound of the formula 1 and is not economical and commercially viable. Besides, separation and purification of compound of the formula 1 from the reaction mixture is difficult and complicated due to the presence of acetone in the reaction mixture. Therefore, it is very difficult and inconvenient to carry out the process.
U.S. Pat. No. 3,694,437 relates to the manufacture of compound of the formula 1 by conversion of Dane salt of the formula 5 to mixed anhydride of the formula 4 and condensing with silyl derivatives of 7-ADCA of the formula 2 obtained by silylation of 7-ADCA of the formula 2. The resulting compound of the formula 6c: ##STR8## wherein R.sub.1 is as defined above and Z.sub.3 is trimethyl silyl group is hydrolysed with an aqueous mineral acid to cleave the silyl group and give the compound of the formula 1. This process also suffers from poor yields (50%) and low purity of compound of the formula 1 and is, therefore, uneconomical and commercially not viable.
U.S. Pat. No. 3,864,340 relates to the manufacture of compound of the formula 1 by reacting 7-ADCA of the formula 2 with triethlyl amine using alcohol in very large excess (ca 26 volumes) as solvent followed by condensation with a mixed anhydride of the formula 4 prepared from an enamine protected Dane salt of the formula 5. The resulting compound of the formula 6d: ##STR9## wherein R.sub.1 is as defined above and Z.sub.4 is triethyl amine is hydrolyzed with an aqueous mineral acid to remove the triethyl amine group and give compound of the formula 1. The process gives the compound of the formula 1 in very low yields (c.a 35-40%) and low purity and is therefore, uneconomical and commercially not viable. Separation and purification of compound of the formula 1 from the reaction mixture is difficult and cumbersome due to the alcohol emulsion. Therefore, it is difficult and inconvenient to carry out the process.
U.S. Pat. No. 4,299,955 relates to the manufacture of compound of the formula 1 by reacting a mixed anhydride of the formula 4 prepared from Dane salt of the formula 5 with avoid chloride of the formula R.sub.2 COCl in acetone with an aqueous alkyl amine solution of 7-ADCA of the formula 2 and a solvent such as dimethyl sulfoxide, dimethyl acetamide, formamide or dimethyl formamide. The resulting compound of the formula 6e: ##STR10## wherein R.sub.1 is as defined above and Z.sub.5 is triethyl amine is hydrolyzed with an aqueous mineral acid to remove the alkyl group and obtain compound of the formula 1. This process is difficult and inconvenient to carry out due to the separation and purification of compound of the formula 1 from the acetone emulsion is difficult and inconvenient. Also the process has been found to give the compound of the formula 1 in poor yields (20%) and low purity and is, therefore, uneconomical and commercially not viable.
European Patent No 0127541 relates to the preparation of salts of amino-beta-lactamic acids by reacting the amino-beta lactamic acids with stoichiometric amount of alkyl guanidines in a solvent at -50 to +25.degree. C. Experimental example 61 of the above European Patent relates to preparation of compound of the formula 1 by reacting potassium N-(1-ethoxycarbonyl propen-2-yl)-alpha-aminophenylacetate (Dane salt) in methylene chloride with gamma-picoline hydrochloride or pyridine or beta-picoline in the presence of N-methylacetamide followed by pivaloyl chloride. The resulting mixed anhydride is condensed with 7-ADCA in methylene chloride and tetramethylguanidine. The excess mixed anhydride was destroyed with diethyl amine. The resulting compound was hydrolysed with aqueous hydrochloric acid and treated with acetonitrile followed by cleavage of the acetonitrile solvate with water to obtain the compound of the formula 1. This process generates an acetonitrile solvate necessitating subsequent cleavage of the solvate with water. This process also uses the Dane salt in large excess (about 20% in excess of 7-ADCA) necessitating destruction of the excess Dane salt with diethyl amine. This process is, therefore, tedious and difficult to carryout. It also results in large amount of unreacted 7 ADCA in the reaction leading to poor yields and is, therefore, uneconomical.